This R01 will establish the biological basis for a novel treatment strategy for schizophrenia (SZ), by identifying biomarkers that predict pro-cognitive drug effects in SZ patients. These pro-cognitive effects would be utilized to specifically enhance the clinical impact of cognitive therapies (CTs) for SZ; similar strategies are being effectively advanced for the treatment of anxiety disorders. This application will test the effects of a challenge dose of the low-affinity NMDA antagonist, memantine (MEM), on sensorimotor gating and neuro- cognition in SZ patients; specific hypotheses will be tested in relation to the moderating impact of physiological and genetic biomarkers on these MEM effects. Predictors of positive effects of MEM will be used to identify enriched MEM-sensitive SZ patient cohorts for trials using MEM to augment the therapeutic effects of CTs. The pharmacotherapy of SZ has been dominated by drugs with limited clinical impact. Some forms of CTs, including the broader formats of cognitive rehabilitation and cognitive training, effectively reduce symptoms and improve function in SZ. The premise of this application is that the benefits of CTs in SZ might be enhanced by drugs that increase specific cognitive abilities, including working memory (WM), even if these pro-cognitive drugs lack clinical impact when administered without CT. The main goal of this application is to develop an innovative intervention strategy that enhances the clinical benefits of CT in SZ through administration of pro-cognitive agents to biomarker-identified sensitive patients. We recently reported that a single dose of the safe, neuroprotective, widely used Alzheimer's disease medication, MEM (20 mg p.o.), significantly increased prepulse inhibition (PPI) of startle in healthy subjects. These PPI-enhancing effects of MEM are associated with: 1) increased WM; and 2) phenotypes linked to the high activity Val158Met COMT polymorphism. PPI is impaired in SZ patients; lowest levels of PPI in patients are associated with: 1) poor functional outcome; and 2) the Val/Val COMT genotype. If our MEM findings in healthy subjects are reproduced in SZ patients, we will detect MEM-associated increases in PPI and WM, particularly among Val/Val patients. We will then be positioned to test the hypothesis that acute PPI and WM-enhancing effects of MEM predict therapeutic benefit of MEM in SZ patients undergoing CT. This application will assess the acute effects of MEM (0 vs. 10 or 0 vs. 20 mg p.o.) in 80 SZ patients and 80 healthy subjects, to test the prediction that MEM will increase PPI and enhance WM in SZ patients, particularly in those characterized by low basal PPI levels and/or the Val/Val COMT genotype. Mismatch negativity and gamma band synchronization will also be assessed as potentially informative MEM-sensitive and functionally relevant biomarkers. Findings from this study will guide future clinical trials testing the overall effectiveness of MEM as an adjunct to CT by identifying biomarker-defined patients most likely to benefit from this therapeutic regimen; the feasibility of such trials is now being tested by the PI's R34 MH093453.